Abstract：
IL-33, which is a crucial modulator of adaptive immune responses far beyond type 2 response, can enhance the function of several T cell subsets and maintain the immune homeostasis. However, the contribution of IL-33 to double negative T (DNT) cell remains unappreciated. Here, we demonstrated that the IL-33 receptor ST2 was expressed on DNT cells, and that IL-33 stimulation increased DNT cells proliferation and survival in vivo and in vitro. Transcriptome sequencing analysis also demonstrated that IL-33 enhanced the biological function of DNT cells, especially effects on proliferation and survival. IL-33 promoted DNT cells survival by regulating Bcl-2, Bcl-xl and Survivin expression. IL-33-TRAF4/6-NF-κB axis activation promoted the transmission of essential division and survival signals in DNT cells. However, IL-33 failed to enhance the expression of immunoregulatory molecules in DNT cells. DNT cells therapy combined with IL-33 inhibited T cells survival and further ameliorated ConA-induced liver injury, which mainly depended on the proliferative effect of IL-33 on DNT cells in vivo. Finally, we stimulated human DNT cells with IL-33, and similar results were observed. In conclusion, we revealed a cell intrinsic role of IL-33 in the regulation of DNT cells, thereby identifying a previously unappreciated pathway supporting the expansion of DNT cells in the immune environment.
摘要：
IL-33是远远超过2型反应的适应性免疫反应的关键调节剂，能增强多个T细胞亚群的功能,维持免疫稳态。然而,IL-33对双阴性T（DNT）细胞的贡献仍未得到重视。这里,我们证明了IL-33受体ST2在DNT细胞上表达，IL-33刺激增加DNT细胞的体内和体外增殖和存活。转录组测序分析还表明IL-33增强了DNT细胞的生物学功能，尤其是对增殖和存活的影响。IL-33通过调节Bcl-2、Bcl-xl和Survivin表达促进DNT细胞存活。IL-33-TRAF4/6-NF-κB轴激活促进DNT细胞中必需分裂和存活信号的传递。然而,IL-33不能增强DNT细胞中免疫调节分子的表达。DNT细胞治疗联合IL-33抑制T细胞存活，进一步改善ConA诱导的肝损伤，这主要取决于IL-33对体内DNT细胞的增殖作用。最后,我们用IL-33刺激人DNT细胞，并观察到类似的结果。总之,我们揭示了IL-33在DNT细胞调节中的细胞内在作用，从而鉴定了以前未被理解的支持DNT细胞在免疫环境中扩增的途径。
